Derivates of 8-aminolevulinic acid (DALA) have recently been the subject of extensive and increased investigation and research, because of their biological effects. New effects have been discovered for derivates of δ-aminolevulinic acid (DALA), such as anti-cancer effect, pesticide effect, and insecticide effect. This results in that derivates of DALA may be used in technical areas, such as anti-cancer agent, pesticide agent, insecticide agent, and as a plant growth factor.
Trans-4-oxo-2-pentenoate is also a compound of great chemical value, and it is therefore of great interest to find easy, economical and time saving methods to manufacture it. Trans-4-oxo-2-pentenoate is a reactive enone, that for example may be used in conjugate addition of ketones and similar compounds, such as for example Robinson annelations.
Neuberger, A. et al., J. Chem. Soc., 1954, p. 1820 describes the use of esters of 5-phtalimidolevulinic acid as precursors of DALA, through elimination of phtalic acid, by hydrolysis.
Lopez, R. F. V., et al., Adv. Drug Delivery Reviews, 56, p. 77-94, 2004, discloses the use of esters of δ-phtalimidolevulinic acid as a substitute for DALA, due to the relative stability in comparison to DALA, for instance when used as a PDT (photodynamic therapy) sensitizer.
Dabrowski Zbigniew et al., “The synthesis and application of 5-aminolevulinic acid derivatives in photodynamic therapy and photodiagnosis”, Acta poloniae pharmaceutica, vol. 60, p. 219 to 224, 2003, describes a method to use ALA-esters in photodynamic therapy and photodiagnosis, in which method 5-bromoleulinate is reacted with phtalimide to obtain 5-phtalimidolevulinate. This method presents a number of disadvantages. Firstly, this method is in need of a distillation of the crude reaction mixture, obtained from the bromination of levulinic acid. Secondly, this method only reacts 5-bromoleulinate with phtalimide, which presents the disadvantage of a need to purify the product in a cumbersome purifying step at a very low temperature, which step is costly and time spending. This purifying step also results in a reaction rest containing brominated contaminations (the brominated contaminations constitute 65% of the used crude material, according to the article). Thirdly, as a result of the reaction steps according to this article, no trans-4-oxo-2-pentenoate is obtained, which compound has a significant economic and scientific value.
Katsumi et al., “Synthesis of 5-[4,5-13C2] and 5-[1,5-13C2]aminolevulinic acid”, Journal of labelled compounds and radiopharmaceuticals, pages 569 to 576, 2002, describes the reaction between phtalimide and ethyl bromo[1,2-13C]acetate. The object in this article is not the same as the present invention, i.e. to obtain phtalimidolevulinic, or succinimidolevulinic, acid and trans-4-oxo-2-pentenoate. Thereby, the steps performed in this article fails to disclose the combined obtainment of said substances. Furthermore, in this respect this article includes a six step manufacturing process of C13 marked ALA, which manufacturing process is totally different from the present invention and has therefore used totally different substances. An intermediate product of this manufacturing process is however similar to one of the final products according to the present invention.
Other documents disclosing the state of the art are U.S. Pat. No. 5,907,058, which describes the manufacturing of aminolevulinic acid, and CN 1056868 and PL 104118, which two documents describes other reactions with phtalimide.
Hence, an improved method of manufacturing esters of dicarboxyimidolevulinic acid and alkyl trans-4-oxo-2-pentenoate (alkyl trans-β-acetylacrylate) would be advantageous and in particular needed to allow an increased yield, cost-effectiveness, time-effectiveness, and ease over the processes according to prior art, and it would be even more advantageous if esters of dicarboxyimidolevulinic acid and alkyl trans-4-oxo-2-pentenoate (alkyl trans-β-acetylacrylate) could be manufactured in the same reaction, said reaction being easy to operate, more economical than the processes according to the prior art, and that is time saving in comparison with the processes according to prior art. Furthermore, it would be of great advantage to provide a method of manufacturing esters of dicarboxyimidolevulinic acid and alkyl trans-4-oxo-2-pentenoate (alkyl trans-β-acetylacrylate) where cumbersome and costly distillation and purifying processes and the obtainment of brominated contaminations, according to the prior art, could be omitted.